VA Class:CN105

AHFS Class:

• Selective Serotonin Agonists 28:32.28

Generic Name(s):

• Frovatriptan Succinate

Chemical Name:

• (+)-( R )-2,3,4,9-tetrahydro-3-(methylamino)-1 H -carbazole-6-carboxamide butanedioate monohydrate

Molecular Formula:

• C₁₄H₁₇N₃O•H₂O

Frovatriptan succinate is a selective agonist of serotonin (5-hydroxytryptamine; 5-HT) type 1B and 1D receptors (“triptan”).1,2

Vascular Headaches

Migraine

Frovatriptan succinate is used for the acute treatment of attacks of migraine with or without aura in adults.1 The manufacturer states that frovatriptan should not be used for the management of hemiplegic or basilar migraine or for the prophylaxis of migraine.1 Safety and efficacy have not been established for the management of cluster headaches.1

Efficacy of frovatriptan administered at the recommended dosage of 2.5 mg has been evaluated for the acute treatment of migraine attacks in several randomized, placebo-controlled studies in adult outpatients with moderate to severe headaches.1,2,3 In these studies, 37-46% of patients receiving frovatriptan achieved a response (mild or no headache pain) 2 hours after treatment, compared with 21-27% of patients receiving placebo.1,2,3 The drug also relieved manifestations of migraine other than headache (including nausea, photophobia, and phonophobia) and reduced the need for supplemental migraine therapy.1

The US Headache Consortium considers 5-HT_1B/1D receptor agonists (e.g., frovatriptan) an appropriate treatment choice for the acute management of moderate to severe migraine headaches in patients without contraindications to these drugs and recommends use of 5-HT_1B/1D receptor agonists, dihydroergotamine, or ergotamine in patients with more severe migraine attacks as well as in patients in whom previous therapy with nonsteroidal anti-inflammatory agents (NSAIAs) or fixed-combination preparations such as acetaminophen, aspirin, and caffeine has been ineffective.4,5

For further information on management and classification of migraine headache, see Vascular Headaches: General Principles in Migraine Therapy, under Uses in Sumatriptan 28:32.28.

General

Frovatriptan succinate is administered orally with fluids without regard to meals.1 Dosage of frovatriptan succinate is expressed in terms of frovatriptan.1

The recommended dosage of frovatriptan for acute treatment of migraine attacks with or without aura in adults is 2.5 mg given as a single dose.1 Higher dosages provide no additional benefit but may increase the risk of adverse effects.1,2

If headache recurs, additional doses of frovatriptan may be administered at intervals of not less than 2 hours, up to a maximum adult dosage of 7.5 mg in any 24-hour period.1 However, additional doses of frovatriptan are unlikely to provide benefit in patients who do not respond to the first dose of the drug for the same headache.1 The safety of treating an average of more than 4 headaches per 30-day period has not been established.1

Special Populations

No special population dosage recommendations at this time.8,9

Contraindications

Known or suspected ischemic heart disease (e.g., angina pectoris, myocardial infarction, silent ischemia), coronary vasospasm (e.g., Prinzmetal variant angina), uncontrolled hypertension, other serious underlying cardiovascular disease, cerebrovascular syndromes (e.g., stroke syndrome, transient ischemic attacks), peripheral vascular disease, or ischemic bowel disease.1 Basilar or hemiplegic migraine.1 Treatment within the previous 24 hours with another 5-HT₁ receptor agonist or with an ergot alkaloid (e.g., ergotamine, dihydroergotamine, methysergide [no longer commercially available in the US]).1 Known hypersensitivity to frovatriptan or any ingredient in the formulation.1

Warnings/Precautions

Careful Diagnosis of Migraine

Frovatriptan should be used only in patients in whom a clear diagnosis of migraine has been established.1 If the first attack of migraine treated with frovatriptan fails to respond to the drug, the diagnosis of migraine should be reconsidered before frovatriptan is administered to treat subsequent attacks.1 Care should be taken to exclude other potentially serious neurologic disorders before frovatriptan is administered to patients not previously diagnosed with migraine or to patients who present with atypical symptoms.21

Cardiac Effects

Serious cardiac events, including acute myocardial infarction and fatal or life-threatening cardiac rhythm disturbances (e.g., ventricular tachycardia or fibrillation), have occurred within a few hours following administration of 5-HT₁ receptor agonists.1,21 Myocardial ischemia/infarction or coronary vasospasm (e.g., Prinzmetal variant angina) may occur even in patients without a history of coronary artery disease.21 Use of frovatriptan is contraindicated in patients with ischemic or vasospastic heart disease.1 (See Cautions: Contraindications.) Therapy with 5-HT₁ receptor agonists should be discontinued if disturbances in cardiac rhythm occur.21

Although sensations of tightness, pain, pressure, and heaviness in the precordium, throat, neck, and jaw occur frequently following administration of 5-HT₁ receptor agonists, these sensations usually are noncardiac in origin.1,21 However, the manufacturer states that patients experiencing symptoms suggestive of angina after receiving frovatriptan should be evaluated for the presence of coronary artery disease or predisposition to Prinzmetal variant angina.1

Patients with multiple cardiovascular risk factors (e.g., postmenopausal women; men older than 40 years of a patients with risk factors such as hypertension, hypercholesterolemia, smoking, obesity, diabetes, or family history of coronary artery disease) who have not previously received therapy with a 5-HT₁ receptor agonist should undergo cardiovascular evaluation prior to initiation of 5-HT₁ receptor agonist therapy.1,21 If the evaluation provides evidence of coronary artery disease or coronary artery vasospasm, the drug should not be administered.1 For patients with a satisfactory cardiovascular evaluation, the manufacturer states that consideration should be given to administration of the first dose in a medically supervised setting with electrocardiographic monitoring performed immediately following administration of the dose.1,21 Periodic cardiovascular evaluation is recommended for patients with risk factors for coronary artery disease who are receiving intermittent long-term therapy with 5-HT₁ receptor agonists.1

For further information on the systematic approach to administering 5-HT₁ receptor agonists in patients with risk factors for the development of coronary artery disease, see Cautions: Precautions and Contraindications, in Sumatriptan 28:32.28.

Cerebrovascular Effects

Cerebral or subarachnoid hemorrhage and stroke, sometimes fatal, have occurred in patients receiving 5-HT₁ receptor agonists.1,21 In a number of cases, it appears possible that the cerebrovascular event was the primary event, and the 5-HT₁ receptor agonist was administered in the mistaken belief that the patient's symptoms were caused by a migraine attack.1 Patients with a history of migraine may be at increased risk for certain cerebrovascular events (e.g., stroke, hemorrhage, transient ischemic attack).1 Therapy with 5-HT₁ receptor agonists should be discontinued in patients experiencing a cerebrovascular event.1,21 (See Cautions: Contraindications.)

Other Cardiovascular or Vasospastic Effects

Noncoronary vasospastic reactions, including peripheral vascular ischemia, GI ischemia and infarction (presenting with abdominal pain and bloody diarrhea), splenic infarction, and Raynaud's syndrome, have been reported in patients receiving 5-HT₁ receptor agonists.1,21 (See Cautions: Contraindications.) Transient or permanent blindness and partial vision loss also have been reported in patients receiving 5-HT₁ receptor agonists, although visual disorders may occur as manifestations of migraine attacks.21 Patients experiencing signs or symptoms suggestive of vasospastic reactions following administration of any 5-HT₁ receptor agonist should be evaluated to rule out vasospastic reactions before receiving additional doses of frovatriptan.1,21

Substantial increases in blood pressure, including hypertensive crisis with acute impairment of organ systems, have been reported rarely following administration of 5-HT₁ receptor agonists in patients with or without a history of hypertension.21 (See Cautions: Contraindications.) Transient increases in blood pressure have been observed following administration of the recommended dosage (2.5 mg) of frovatriptan in geriatric patients.1

Increases in mean pulmonary arterial pressure have been observed following administration of another 5-HT₁ receptor agonist to patients with suspected coronary artery disease who were undergoing cardiac catheterization.1

Serotonin Syndrome

Potentially life-threatening serotonin syndrome has been reported in patients receiving 5-HT₁ receptor agonists, particularly in those receiving concomitant therapy with selective serotonin-reuptake inhibitors (SSRIs) or selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs).1,11 Serotonin syndrome also may occur in patients receiving 5-HT₁ receptor agonists concomitantly with monoamine oxidase (MAO) inhibitors or tricyclic antidepressants.21 Symptoms of serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or GI symptoms (e.g., nausea, vomiting, diarrhea).1,11 If concurrent therapy with a 5-HT₁ receptor agonist and an SSRI or SNRI is clinically warranted, the patient should be observed carefully, particularly during initiation of therapy, when dosage is increased, or when another serotonergic agent is initiated.1,11 If manifestations of serotonin syndrome occur, treatment with frovatriptan and any concurrently administered serotonergic agents should be discontinued and supportive and symptomatic treatment should be initiated.33

Medication Overuse Headache

Excessive use of drugs indicated for the management of acute migraine attacks (e.g., use of 5-HT₁ receptor agonists, ergotamine, opiates, or certain analgesic combinations on a regular basis for 10 or more days per month) may result in migraine-like daily headaches or a marked increase in the frequency of migraine attacks.21,31,32 Detoxification, including withdrawal of the overused drugs; treatment of withdrawal symptoms (which often include transient worsening of headaches); and consideration of prophylactic therapy for migraine attacks may be necessary.21,31,32

Ocular Effects

Accumulation of frovatriptan and/or its metabolites in melanin-rich tissues (such as the eye) may occur over time, resulting in potential toxicity in these tissues with extended use.1

Specific Populations

Pregnancy

Category C.1 (See Users Guide.)

Lactation

Frovatriptan and/or its metabolites are distributed into milk in rats.1 Caution is advised if used in nursing women.1

Pediatric Use

Safety and efficacy of frovatriptan have not been established in children younger than 18 years of age.1

Geriatric Use

Experience with frovatriptan in those 65 years of age and older is insufficient to determine whether they respond differently than younger adults.1 Although plasma concentrations of frovatriptan reportedly were substantially (1.5- to 2-fold) higher in geriatric patients than in younger adults,1,3,9 elimination half-life was similar between the 2 groups, and no adjustments in frovatriptan dosage appear to be necessary in geriatric patients.8,9

Hepatic Impairment

Mean area under the blood concentration-time curve (AUC) of frovatriptan reportedly was approximately twofold higher in patients with mild to moderate hepatic impairment than in healthy individuals;1,9 although no dosage adjustments are necessary, frovatriptan should be used with caution in these patients.8,9 Frovatriptan has not been studied in patients with severe hepatic impairment.1

Common Adverse Effects

Adverse effects occurring in 2% or more of patients receiving frovatriptan and more frequently than placebo include dizziness,1 fatigue,1 headache,1 paresthesia,1 flushing,1 dry mouth,1 hot or cold sensation,1 skeletal pain,1 dyspepsia,1 chest pain,1 somnolence,1 and nausea.1

Drugs Affecting Hepatic Microsomal Enzymes

Frovatriptan appears to be metabolized principally by cytochrome P-450 (CYP) isoenzyme 1A2.1,10 Frovatriptan does not inhibit or induce CYP1A2 in vitro, suggesting that the drug is unlikely to alter its own metabolism or the pharmacokinetics of other drugs metabolized by this enzyme.1,10 Although concomitant administration of frovatriptan with drugs that inhibit CYP1A2 (e.g., fluvoxamine, propranolol, oral contraceptives) has resulted in increases in blood concentrations of frovatriptan, these effects are not considered to be clinically relevant, and dosage adjustments generally are not necessary.1,8,10

Ergot Alkaloids and Other 5-HT1 Receptor Agonists

Potential pharmacologic interaction (additive vasospastic effects) when frovatriptan is used concomitantly with ergot alkaloids (e.g., ergotamine, dihydroergotamine, methysergide [no longer commercially available in the US]) and other 5-HT₁ receptor agonists.1 Use within 24 hours is contraindicated.1

Selective Serotonin-reuptake Inhibitors and Selective Serotonin- and Norepinephrine-reuptake Inhibitors

Potential pharmacologic interaction (potentially life-threatening serotonin syndrome).1,11 If concomitant use is clinically warranted, the patient should be observed carefully, particularly during treatment initiation, when dosage is increased, or when another serotonergic agent is initiated.1,11 (See Serotonin Syndrome under Cautions: Warnings/Precautions.)

Potential pharmacokinetic interaction with fluvoxamine (increased blood concentrations of frovatriptan).10 Dosage adjustments are not necessary. 8,10

Oral Contraceptives

Potential pharmacokinetic interaction (increased blood concentrations of frovatriptan);1,10 no dosage adjustments are necessary.8,9

Propranolol

Potential pharmacokinetic interaction (increased blood concentrations of frovatriptan);1,3,10 no dosage adjustments are necessary.8,10

Pharmacokinetics

Absorption

Bioavailability

Incompletely absorbed from GI tract; absolute bioavailability of 20 and 30% in males and females, respectively.1,9

Peak plasma concentrations attained approximately 2-4 hours after oral administration.1,9

Food

Food does not affect bioavailability but may delay time to peak plasma concentration by 1 hour.1

Distribution

Extent

Distributes into cellular fraction of blood, principally erythrocytes (approximately 60% reversibly bound).9

Animal studies indicate limited capacity to cross blood-brain barrier.9

Distributed into milk in rats; not known whether distributed into milk in humans.1

Plasma Protein Binding

Approximately 15%.1,9

Elimination

Metabolism

Appears to be metabolized principally via CYP1A2 to numerous metabolites, including desmethyl frovatriptan, which exhibits lower affinity for 5-HT_1B/1D receptors compared with frovatriptan.1,3

Elimination Route

Excreted in urine (32%) and feces (62%) as unchanged drug and metabolites.1

Half-life

Approximately 26 hours.1,9

Special Populations

In patient with mild to moderate hepatic impairment, AUC is twofold higher than in healthy individuals; pharmacokinetics not studied in patients with severe hepatic impairment.1

In geriatric patients, AUC is 1.5- to 2-fold higher than in younger adults; half-life and time to peak plasma concentrations unchanged.1

Description

Frovatriptan succinate is a selective agonist of serotonin (5-hydroxytryptamine; 5-HT) type 1B and 1D receptors.1,2 Frovatriptan is structurally distinct from, but pharmacologically related to, other selective 5-HT_1B/1D receptor agonists (e.g., almotriptan, eletriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan).2,7,8 Because the mechanisms involved in the pathogenesis of migraine are not clearly understood, the precise mechanism of action of 5-HT₁ receptor agonists in the management of migraine has yet to be established.6 However, current data suggest that 5-HT₁ receptor agonists, including frovatriptan, may ameliorate migraine through selective constriction of certain intracranial blood vessels, inhibition of neuropeptide release, and/or reduced transmission in the trigeminal pain pathway.1,2

In vitro, frovatriptan is metabolized principally by cytochrome P-450 (CYP) isoenzyme 1A2 to numerous metabolites, including desmethyl frovatriptan, which exhibits a lower affinity for 5-HT_1B/1D receptors compared with the parent drug.1,3 The activity of other metabolites (e.g., hydroxylated frovatriptan, N -acetyl desmethyl frovatriptan, hydroxylated N -acetyl desmethyl frovatriptan) has not been fully elucidated.1 Following oral administration of a single 2.5-mg dose of radiolabeled frovatriptan, 32 and 62% of the dose is excreted in urine and feces, respectively, as unchanged drug and metabolites.1 The elimination half-life of frovatriptan is reportedly 26 hours in healthy individuals.1,8

Advice to Patients

Risk of dizziness or fatigue; importance of exercising caution when driving or operating machinery.1

Risk of serious cardiovascular or cerebrovascular events (e.g., myocardial infarction, stroke) or other vasospastic reactions.1 Importance of seeking medical care if symptoms of such reactions (e.g., shortness of breath, weakness, slurring of speech, sudden or severe abdominal pain, difficulty in seeing, or tightness, pain, pressure, or heaviness in chest, throat, jaw, or neck) occur after taking frovatriptan and of not taking frovatriptan again until evaluated by clinician.1,8,21

Importance of adhering to prescribed directions for use.1 Provide copy of manufacturer's patient information.1

Overuse of drugs indicated for the management of acute migraine attacks may exacerbate headaches; importance of recording headache frequency and drug use to monitor effectiveness of treatment.21,31

Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses (e.g., cardiovascular disease).1

Importance of informing patients of risk of serotonin syndrome, particularly with concurrent use of frovatriptan and a selective serotonin-reuptake inhibitor (SSRI) or selective serotonin- and norepinephrine-reuptake inhibitor (SNRI).1,11 Importance of seeking immediate medical attention if symptoms of serotonin syndrome develop.11

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

Importance of informing patients of other important precautionary information.1 (See Cautions.)

Additional Information

Overview^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

1. Endo Pharmaceuticals Inc. Frova^® (frovatriptan succinate) tablets prescribing information. Chadds Ford, PA; 2012 Dec.

2. Tfelt-Hansen P, De Vries P, Saxena PR. Triptans in migraine: a comparative review of pharmacology, pharmacokinetics, and efficacy. Drugs . 2000; 60:1259-87. [PubMed 11152011]

3. Jhee SS, Shiovitz T, Crawford AW et al. Pharmacokinetics and pharmacodynamics of the triptan antimigraine agents: a comparative review. Clin Pharmacokinet . 2001; 40:189-205. [PubMed 11327198]

4. Matchar DB, Young WB, Rosenberg JH et al. Evidence-based guidelines for migraine headache in the primary care setting: pharmacological management of acute attacks. St. Paul, MN; 2001. From American Academy of Neurology web site ([Web]). [Web]

5. Silberstein SD, for the US Headache Consortium. Practice parameter: evidence-based guidelines for migraine headache (an evidence-based review): report of the quality standards subcommittee of the American Academy of Neurology. Neurology . 2000; 55:754-63. [PubMed 10993991]

6. GlaxoWellcome. Amerge^® (naratriptan hydrochloride) tablets prescribing information. Research Triangle Park, NC; 1999 Nov.

7. Deleu D, Hanssens Y. Current and emerging second-generation triptans in acute migraine therapy: a comparative review. J Clin Pharmacol . 2000; 40:687-700. [PubMed 10883409]

8. Elan Pharmaceuticals, South San Francisco, CA: Personal communication.

9. Buchan P, Keywood C, Wade A et al. Clinical pharmacokinetics of frovatriptan. Headache . 2002; 42(Suppl 2):S54-62.

10. Buchan P, Wade A, Ward C et al. Frovatriptan: a review of drug-drug interactions. Headache . 2002; 42(Suppl 2):S63-73.

11. Food and Drug Administration. Public health advisory: combined use of 5-hydroxytryptamine receptor agonists (triptans), selective serotonin reuptake inhibitors (SSRIs) or selective serotonin/norepinephirne reuptake inhibitors (SNRIs) may result in life-threatening serotonin syndrome. Rockville, MD; 2006 Jul 19. From the FDA website: ([Web], [Web], and [Web]).

21. Merck and Co., Inc. Maxalt^® (rizatriptan benzoate) tablets and Maxalt-MLT^® (rizatriptan benzoate) orally disintegrating tablets prescribing information. Whitehouse Station, NJ; 2013 Jan.

31. Tepper SJ, Tepper DE. Breaking the cycle of medication overuse headache. Cleve Clin J Med . 2010; 77:236-42. [PubMed 20360117]

32. Negro A, Martelletti P. Chronic migraine plus medication overuse headache: two entities or not?. J Headache Pain . 2011; 12:593-601. [PubMedCentral][PubMed 21938457]

33. Bijl D. The serotonin syndrome. Neth J Med . 2004; 62:309-13. [PubMed 15635814]